This invention relates to implantable devices such as tissue engineering scaffolds.
Many complex animal tissues cannot regenerate after certain injury or disease. In other cases, animal tissues are damaged or malformed due to congenital or developmental defects. One approach to repairing tissue in these cases is known as tissue engineering. Tissue engineering is performed by providing a “scaffold” which serves as a matrix upon which cells can grow. Tissue structures are formed in vitro by growing cells on the scaffold. The structures can then be implanted into living organisms to repair natural tissues that have been damaged by disease or injury. Implantable devices of these types are of interest for repairing bone, ligaments, dental ligaments, tendons, epidermal tissue, muscle tissue (including cardiac tissue) and in other applications.
The scaffold material is usually a three-dimensional, porous structure. Porous polymers have attracted increased interest in the field of tissue engineering, because porous polymers have unique physicochemical properties, which can provide three dimensional structures as scaffolds to guide cell growth and tissue development. The ability of a cell to migrate and attach to a substrate or scaffold surface is an important attribute of the scaffold material. In addition, the scaffold material must be biocompatible and nontoxic.
Certain polymers are known to be highly biocompatible. Examples of these polymers include poly-L-lactic acid (or poly-L-lactide), copolymers of L-lactic acid or L-lactide with other alpha-hydroxyacids such as glycolic acid; copolymers of L-lactic acid or L-lactide with ethylene glycol; polyesters such as poly(ε-caprolactone), poly(3-hydroxybutyrate), poly(s-caproic acid), poly(p-dioxanone) and certain poly(ortho esters) such as polyol/diketene acetals addition polymers. These have been suggested for use as scaffold materials in, for example, U. S. Published Patent Application 2006/0263335 and 2007/0276509. Collagenous materials often are biocompatible and have been suggested for use as scaffold materials, for example, in U.S. Pat. No. 7,338,517.
The porous structure of pure polymers adversely impacts their mechanical properties and biocompatibility. Ceramics such as aluminum oxide and titanium oxide have excellent biocompatibility and bonds well to bone. See, e.g., K. Rezwan et al., “Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering”, Biomaterials, 27 (2006) 3413; H. Warashina et al., “Biological reaction to alumina, zirconia, titanium and polyethylene particles implanted onto murine calvaria”, Biomaterials, 24 (2003) 3655; and Y. Takami et al., “Biocompatibility of alumina ceramic and polyethylene as materials for pivot bearings of a centrifugal blood pump”, Journal of Biomedical Materials Research, 36 (1997) 381. The inclusion of bioactive ceramic compositions in polymer substrates may reinforce the porous structures of the pure polymer and enhance the bioactivity and the tissue interaction. Therefore, hybrid three-dimensional porous scaffolds of synthetic or naturally derived biodegradable polymers and ceramics may be useful as bone replacement materials or as scaffolds for bone regeneration composition. These hybrid materials potentially exhibit favorable mechanical properties and bioactivity so that they can receive and respond to specific biological signals that direct and promote cell adhesion, proliferation and differentiation, and tissue regeneration.
In many practical applications, porous polymer/ceramic composites are often produced via incipient wetting methods such as casting, porogen leaching, and gas foaming. The solvent-based methods have the risk of leaving potentially toxic organic solvent residues. Dispersing micro-sized or nano-sized ceramic particles in the polymer matrix is another method that has been proposed to fabricate the polymer/ceramic composites. However, a potential negative effect of nanoparticle-containing scaffolds is the possibility of migration of nanoparticles within the body and their distribution via the blood stream, leading to pathologies of unknown origin. See, e.g., L. C. Gerhardt et al., “Titanium dioxide (TiO2) nanoparticles filled poly(D,L lactic acid) (PDLLA) matrix composites for bone tissue engineering”, Journal of Materials Science-Materials in Medicine, 18 (2007) 1287.
Therefore, there is a desire to produce a porous polymer/ceramic composite that is biocompatible, exhibits little toxicity towards cells (particularly mammalian cells and especially human cells) or the organism as a whole, and which has good mechanical properties. The composite should be a material to which cells and/or bone tissue can become easily attached. To accomplish this, the composite should have the ceramic material coated onto both the interior surfaces (i.e., the surfaces of the pores) as well as the exterior surfaces, and the pore size should be such that cells can migrate into the pores and become attached there.